The proposed 5-year project uses an integrated brain/behavior framework to determine long-term effects of iron deficiency anemia (IDA) in infancy. The project will evaluate approximately 1300 16-year-old Chilean adolescents, followed since infancy, including 200 who will receive sophisticated neurophysiologic assessments. Specific Aims are: 1) to test the hypothesis that early IDA will increase vulnerability to subsequent insults and stressors (i.e., "fragile recovery"), specifically adolescence with its dramatic brain maturation and expectable physical, social, and academic stressors;2) to characterize interconnections among neuromaturation alterations and assess their functional significance;and 3) to identify genetic factors that increase susceptibility to iron deficiency and its effects. We expect that brain and behavior systems showing marked changes in adolescence, particularly those involving dopamine (DA) systems, will be particularly sensitive to early IDA (e.g., sleep-wake patterns, motor performance, neuroendocrine patterns, affective responses, reward system, and executive function) (Aim 1). We also predict that former IDA adolescents, who already show altered sleep-wake patterns, will have more social-emotional and neurocognitive disruptions with school day v. holiday/weekend cycle shifts. Neurophysiology studies will be performed for 200 subjects (half-day session for sensory evoked potentials &neurocognitive testing (some with ERP);2 consecutive nights with polysomnography and sequential neuroendocrine sampling;7-day activity monitoring at home). All 1300 subjects will receive a half-day test battery derived from our brain/behavior framework. For Aim 2, sleep-wake patterns, motor activity, heart rate and heart rate variability, and stress-response and night-time cortisol and prolactin patterns will be jointly analyzed. Development of the sophisticated data analytic methodology needed for this aim will start with neurophysiology data available for over 200 subjects at 10 years. The resulting methods will be applied to the 16-year data as they are completed. Aim 3 focuses on functional polymorphisms related to iron regulation (e.g., transferrin, HFE, etc.) and interactions between IDA and variants related to DA, 5-HT, anxiety/depression, ADHD, substance use and risk-taking (e.g., COMT, DRD4, 5-HTTLPR, etc.). All 1300 subjects are involved in order to detect gene-nutrition (IDA in infancy) interactions. The proposed study is the only long-term follow-up of a randomized trial of preventing IDA in infancy. The study will also continue to make unique contributions with its neuromaturation approach and will enter new territory by considering neurophysiologic regulatory processes and genetic vulnerabilities to iron deficiency and its effects. This study remains at the forefront of understanding long-term brain and behavioral effects of iron deficiency in the human infant. Iron deficiency is the world's most common single nutrient disorder;20-25% of the world's infants have iron deficiency anemia and at least as many have iron deficiency without anemia. Long-term ill effects continuing into adolescence, despite iron therapy in infancy, could therefore have major public health implications.